We propose to conduct a genetic epidemiology haplotype association project evaluating polymorphisms of genes in the NER and cell cycle control pathways in a series of NSCLC cases and controls. The ability to identify individuals with the highest risk of developing tobacco-related cancers, most importantly lung cancer, has important public health and clinical implications for screening, early detection, prevention and treatment. In addition to variability in activation and detoxification pathways of mutagenic agents, there is a very strong biologic rationale to also study the variability in the capacity to repair smoking induced DNA damage as another major family of susceptibility biomarkers. The nucleotide excision repair (NER) pathway is important in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this pathway and mutations in the XPD gene, including the common A35931C (Lys751Gln) variant allele, result in reduced repair capacity. Furthermore, regulation of the cell cycle control mechanism can influence the potential for increased cell proliferation and the promotion of genetic instability. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. Our initial case/control studies have demonstrated a significant association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1 870A variant allele and XPD Gin allele (OR=7.1, 95%CI 4.0-12.5). We propose to extend these observations to include a pathway haplotype association analysis, focusing on all of the 25 genes involved in the NER pathway and 5 key cell cycle control genes, in order to capture all of the common genetic variation within the selected genes in the two pathways of interest and evaluate how this variation contributes to lung cancer risk. To test the prognostic significance of these haplotypes, we will also perform a prospective study by genotyping the PLuSS and Moffitt Cancer Center High-Risk sub-cohorts. We will also develop a final predictive model by combining the datasets from the case/control and prospective studies in Specific Aims 2 and 3 for purposes of external validation. The NER gene haplotypes may not only predict lung cancer risk, but also drug resistance and survival. It is well known that resistance to platinum-based drugs, a chemotherapeutic regimen often used in the treatment of lung cancer, is associated with up-regulation of NER proteins. In order to further evaluate the haplotype/phenotype relationship, we propose to study the relationship of the NER haplotype with response to platinum-based drug treatment among the lung cancer cases. This haplotype-based approach will provide a great amount of information about genes and pathways and will help to evaluate how genetic variation relates to lung cancer risk. The ability to rapidly screen individuals for risk and prognosis, using non-invasive procedures, has tremendous potential for future clinical application.